HIV-associated thrombotic microangiopathy (TMA) is a syndrome characterized by intravascular platelet aggregation and thrombus formation. Other precipitants of TMA include certain bacterial infections, drugs, radiation, and pregnancy. All forms of TMA appear to involve a common pathway of antecedent endothelial injury; however, the molecular pathogenesis of HIV- associated TMA remains ill-defined. HIV infects endothelial cells in vitro, and viral protein has been detected in the vascular wall of a patient with TMA, but it remains unclear whether endothelial dysfunction results primarily from viral infection, binding by released viral proteins, and/or through interactions of endothelial cells with HIV envelope protein gp120 mediates cell recognition and viral entry; released gp120 may bind cell surface receptors, alter cellular functions, or cause cellular injury through he activation of humoral and cellular immune responses. Progress in the understanding of HIV-associated TMA and the improvement of therapeutic modalities has been hampered by the lack of in vivo models that adequately reproduce the human disease. This project will characterize molecular mechanisms involved in HIV-associated TMA and facilitate the development of in vivo models of this syndrome. Variants of the HIV envelope protein gp120 associated with TMA will be isolated, their ability to activate human endothelial cells will be analyzed, and their corresponding receptor on endothelial cells will be cloned. Verotoxin, a bacterial toxin known to trigger TMA through endothelial cell injury, will be used in a comparative manner throughout the study. To model the adhesion of HIV-infected cells to activated endothelial cells, leukocytes will be engineered to recognize an damage activated endothelial cells. These studies will further delineate the pathophysiology of HIV-associated TMA and facilitate the design of novel therapeutic interventions.